Unlocking the clock: a systematic review and meta-analysis on optimizing immune checkpoint inhibitor timing for...

Emerging evidence from observational studies suggests that the time-of-day of immune checkpoint inhibitor (ICI) infusion may influence efficacy. This study sought to quantitatively evaluate the impact of ICI infusion timing on the outcomes of patients with solid tumors through a systematic review and meta-analysis.

We systematically searched Embase, PubMed, and Scopus for articles published before April 1, 2026, that compared the efficacy outcomes between early and late time-of-day ICI administration. The primary endpoints were overall survival and progression-free survival. The secondary outcomes included objective response rates and immune-related adverse events. Hazard and risk ratios were pooled using the random-effects model.

Forty-three retrospective cohort studies involving 11,941 patients were included. Pooled analysis revealed a significant association between early time-of-day infusion and improved OS (HR = 0.60, 95% CI: 0.53-0.67) and PFS (HR = 0.65, 95% CI: 0.57-0.73). ORR was also higher (RR = 1.37, 95% CI: 1.21-1.54). No significant differences were observed for any-grade irAEs (RR = 0.98, 95% CI: 0.73-1.32) or grade ≥3 irAEs (RR = 0.95, 95% CI: 0.62-1.46). However, significant publication bias was detected (Egger's test, p < 0.001); after trim-and-fill adjustment, the OS association remained significant (adjusted HR = 0.79, 95% CI: 0.71-0.89), whereas PFS was attenuated and its confidence interval reached the null boundary after rounding (adjusted HR = 0.89, 95% CI: 0.79-1.00).

This meta-analysis suggests significant association between early time-of-day ICI administration and improved efficacy outcomes. These findings must be interpreted with caution, as the evidence base is composed entirely of observational studies with inherent risks of bias, and the presence of publication bias may have led to an overestimation of the observed effect size. While current evidence is insufficient to warrant an immediate change in clinical practice, it provides a compelling rationale for the design of future prospective trials to validate these findings.